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Review
. 2022 Mar;28(3):194-209.
doi: 10.1016/j.molmed.2021.12.008. Epub 2022 Jan 22.

NK cells in the brain: implications for brain tumor development and therapy

Agisilaos Balatsoukas  1 , Filippo Rossignoli  2 , Khalid Shah  3
Affiliations
Review

NK cells in the brain: implications for brain tumor development and therapy

Agisilaos Balatsoukas et al. Trends Mol Med. 2022 Mar.

Abstract

Natural killer (NK) cells are innate lymphoid cells with robust antitumor functions rendering them promising therapeutic tools against malignancies. Despite constituting a minor fraction of the immune cells infiltrating tumors in the brain, insights into their role in central nervous system (CNS) pathophysiology are emerging. The challenges posed by a profoundly immunosuppressive microenvironment as well as by tumor resistance mechanisms necessitate exploring avenues to enhance the therapeutic potential of NK cells in both primary and metastatic brain malignancies. In this review, we summarize the role of NK cells in the pathogenesis of tumors in the brain and discuss the avenues investigated to harness their anticancer effects against primary and metastatic CNS tumors, including sources of therapeutic NK cells, combinations with other treatments, and novel engineering approaches for augmenting their cytotoxicity. We also highlight relevant preclinical evidence and clinical trials of NK cell-based therapies.

Keywords: NK cells; glioblastoma; immunotherapy of the brain, clinical immunotherapy; neuroimmunology.

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Conflict of interest statement

Declaration of interests K.S. owns equity in and is a member of the Board of Directors of AMASA Therapeutics, a company developing stem cell-based therapies for cancer. K.S.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. The other authors declare that they have no competing interests.

Figures

Figure 1:
Figure 1:. NK cell activating and inhibitory receptors with their cognate ligands and downstream signaling.
Activating receptors (in green) recognize ligands mostly encountered in abnormal cells and usually associate with adaptor proteins (e.g., FcεRIγ, CD3ζ, DAP12) containing immunoreceptor tyrosine-based activation motifs (ITAMs). In contrast, inhibitory receptors (in red) detect ligands found on normal cells and typically have immunoreceptor tyrosine-based inhibition motifs (ITIMs) on their cytoplasmic tail. Signals from these two types of receptors integrate at the molecular level in a phosphorylation–dephosphorylation equilibrium, regulating the activity of NK cells. Regulatory cytokines such as IL-2, IL-15, and type I IFN prime NK cells by augmenting signaling downstream of activating receptors, while IL-12, IL-18, and IL-21 promote NK cell cytotoxicity and stimulate IFNγ secretion. Furthermore, IL-21, IL-15, and FMS-related tyrosine kinase 3 ligand (FLT3L) enhance the differentiation, expansion, and effector function of NK cells. In contrast, other cytokines, such as IL-10 and TGFβ, dampen NK cell responsiveness and functions. In addition, recruitment of NK cells to tissues, including tumors, is delegated to the signaling of receptors such as CXCR3, CXCR4, CCR2–CCR5, and CX3CR1.
Figure 2:
Figure 2:. Representative activation pathways and effector functions of NK cells.
(a) Upon encounter with healthy cells, inhibitory signals (red arrows) in NK cells override activating signals (green arrow), resulting in tolerance. (b) Aberrant cells typically become susceptible to NK cell–mediated cytotoxicity via upregulation of activating ligands (“induced-self” response) or (c) via downregulation of inhibitory ligands such as self HLA class I molecules (“missing-self” response). (d) Paucity of inhibitory signaling also accounts for the “non-self” response, in which cytotoxicity is triggered primarily because of the mismatch between inhibitory KIR and allogeneic HLA molecules. (e) In antibody-dependent cell-mediated cytotoxicity (ADCC), IgG opsonization renders target cells (e.g., malignant cells) susceptible to NK cell–mediated lysis through engagement of CD16 (FcγRIIIA). (f) Effector functions of activated NK cells include exocytosis of perforin- and granzyme-containing granules, which induce apoptosis or inflammation-provoking pyroptosis of target cells; expression of FASL and TRAIL, which elicit target cell apoptosis; and cytokine and growth factor secretion (e.g., IFNγ, TNF, GM-CSF, CCL5, XCL1, FLT3L), which not only mediates or accentuates cytotoxic effects but also orchestrates the antitumor immune response by recruiting other immune cells (e.g., dendritic cells), thus facilitating coupling of the innate with the adaptive immune response.
Figure 3:
Figure 3:. NK cell presence in the brain in the context of neuroimmune communication.
(a) Schematic overview of the major immune pathways leading in and out of the CNS. Lymphatic drainage of brain-derived antigens and antigen-presenting cells allows activation of peripheral T cells, which then enter the CNS through “immune gateways” (i.e., leptomeningeal vessels, perivenular area of BBB, and choroid plexus epithelium). These are areas of induced MHC expression in specialized antigen-presenting cells, which interact with activated CD4+ T cells crossing the BBB; in case of antigen recognition, the ensuing inflammatory response allows immune cells to access the CNS parenchyma. Of note, the CSF-drained meningeal and ventricular compartments are more immunologically active, as opposed to the significantly less exposed parenchyma. (b) Recruited by chemokines such as CX3CL1, CCL2, and CXCL10, NK cells enter the CNS through the BBB and the choroid plexus, settling predominantly in the parenchyma and making up a minor fraction of the brain immune cells. They belong mostly to the immature CD16−CD56bright subtype, and their cytotoxic capacity is inhibited upon exposure to norepinephrine (acting on β-adrenergic receptors) and acetylcholine, whereas it is stimulated by glutamate, brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4.
Figure 4:
Figure 4:. Immunosuppressive effects on NK cells in glioblastoma.
Within the TME, NK cells face an intricate immunosuppressive network contributing to tumor resistance. Influenced by GBM-secreted factors, TAMs derived from microglia and circulating monocytes acquire an anti-inflammatory and pro-tumorigenic M2-like phenotype. They secrete TGFβ and IL-10, inhibiting immune cells and recruiting Treg cells while widespread PDL1 expression further blunts the antitumor response. Adenosine produced from extracellular ATP by the action of ectonucleotidase CD39 on Treg cells and TAMs, and CD73 on glioma cells exerts a variety of immunosuppressive effects, including inhibition of NK cells through the A2a adenosine receptor. Cholesterol 25-hydroxylase converts cholesterol to 25-hydroxycholesterol, which suppresses NK cell metabolism by inhibiting sterol regulatory element-binding protein (SREBP), a key transcription factor. Hypoxia and low nutrient levels also impair NK cell activity. PGE2 inhibits the NK cell–mediated DC recruitment, thus abrogating the antitumor effects of the DC–NK cell crosstalk, while lactic acid hampers NK cell activity by reducing the expression of perforin and granzyme B. Further tumor-associated factors compromising NK cells include cyclooxygenases, nitric oxide, kynurenine, GDF15, RTF, and arginine depletion. The panel in the bottom right corner details the membrane interface between GBM and NK cells, illustrating resistance mechanisms such as downregulation of NK cell activating receptors, reduced expression of NKG2DLs and CD95, as well as expression of LLT1 and non-classical HLA class I molecules. In IDH-mutant gliomas, R-2HG mediates epigenetic effects culminating in reduced CXCL9 and CXCL10 expression and diminished chemoattraction of tumor-infiltrating lymphocytes, including NK cells.
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